Frigostable composition for iontophoretic transdermal delivery of a triptan compound

ABSTRACT

The present invention relates to frigostable compositions suitable for iontophoretic transdermal delivery of a triptan compound. The inventive compositions include a salt of a triptan compound, preferably sumatriptan succinate, a polyamine, a dicarboxylic acid, and water or an aqueous solvent mixture, with the composition being free of monocarboxylic acids. The invention further relates to the use of the composition as an integral component of an iontophoretic patch, preferably as an anodic reservoir of the patch.

FIELD OF INVENTION

The present invention relates to frigostable compositions suitable foriontophoretic transdermal delivery of a triptan compound, preferablySumatriptan.

BACKGROUND ART

The transdermal route of parenteral administration provides manyadvantages over other routes of administration. Methods and devices foradministering drugs through the skin are well known in the field ofpharmaceuticals. Typically, transdermal administration is effected byusing passive transdermal systems (e. g. Transdermal TherapeuticSystems, TTS) which deliver drug substances through the skin at definedrates by diffusion processes. Therefore, transdermal drug delivery isvery inefficient for certain types of drug substances. In particular,ionized drugs are often unable to passively permeate through the skin attherapeutically effective rates.

The process of iontophoresis was originally described by LeDuc in 1908,and even earlier in U.S. Pat. No. 222,276 (1879) and U.S. Pat. No.486,902 (1892). Since then, iontophoresis has found commercial use inthe delivery of ionically charged therapeutic drug molecules such aspilocarpine, lidocaine, dexamethasone and fentanyl.

Generally, iontophoresis is a delivery method which relies on the basicprinciple that application of electric current can provide externalenergy to enable or enhance the passage of drug ions across the skin,presumably by increasing drug permeability through the membranes of theskin. When ions bearing a positive charge (e. g. cationic active agents)are placed into or under the anode of an iontophoretic system, theseions will then—upon application of current—be forced to move away fromthe anode and, following the direction of the electrical field, towardsthe cathode which is placed on an adjacent skin area. During thisprocess, transport of the cationic drug through the skin is enhanced orfacilitated. Iontophoresis may be used with different forms of activepharmaceutical ingredients, most favorably with those carrying anelectrical charge, which are thus directly moved across barriers (e. g.the skin) within an electrical field.

In iontophoresis, different to diffusion-controlled transdermal deliverydescribed above, the skin contact area of the device and the activeingredient concentration within the device are less important withrespect to the level of skin flux of the active ingredient. The deliveryof active ingredient through the skin is largely dependent on theapplied current by which the active ingredient can be forced into theskin.

A typical iontophoretic drug delivery system includes an electrolyticelectrical system comprising an anode and a cathode to be adhered todifferent—preferably adjacent—skin areas of a patient, each electrodebeing connected by a wire to a remote power supply, generally amicroprocessor-controlled electrical instrument. Such types of deviceshave been published, including systems with a lean construction (e. g.U.S. Pat. No. 5,685,837 or 6,745,071) as well as more sophisticatedsystems, which systems are basically known to the expert. Iontophoretictransdermal systems for lidocaine and fentanyl are introduced into theUS market.

Transdermal drug transport by iontophoresis is a complex process whichmay be affected by a variety of parameters, such as the concentration ofelectrolytes, ionic strength, the type, composition and viscosity of theelectrode material, the duration of iontophoresis, skin resistance, orarea size of the electrodes. In general, little is known about thevarious influences of these parameters on the iontophoretic process.

Furthermore, in order to meet the strict galenic requirements,transdermal iontophoretic devices must contain defined electrolyteconcentrations having defined ionic strengths, in order to ensure thatthe active substance is transported into the skin at a desired andconstant rate, and to ensure that the transdermally administered dose isboth safe and therapeutically effective.

EP-A 2 285 362 describes compositions for transdermal iontophoreticdevices wherein the compositions comprise a polyamine or polyamine salt,e.g. Eudragit® E 100 which accounts for the above galenic requirements.

The “Zecuity®-Patch” (TEVA Pharmaceuticals Industries, Ltd.), asumatriptan iontophoretic transdermal system for the acute treatment ofmigraine seems to fulfill the above galenic requirements. However, thissumatriptan composition is instable at low temperatures. It requiresstorage and shipping conditions of 15° C. or higher. Exposition of thesumatriptan composition to temperatures of lower than 15° C. leads to anirreversible liquefaction (loss of viscosity, “leaking” patch) of thecomposition and a precipitation of lauric acid.

In view of the above, it is therefore one major object of the presentinvention to provide a triptan composition, preferably a Sumatriptancomposition that is stable at low temperatures, specifically attemperatures at or below 15° C. (frigostability). Specifically it is anobject to avoid a precipitation of crystals and to maintain or evenincrease the viscosity of the triptan composition compared to theoriginal Zecuity formulation.

SUMMARY OF THE INVENTION

In view of the above object, the present invention provides improvedcompositions for iontophoretic transdermal delivery of a triptancompound, preferably sumatriptan.

The sumatriptan iontophoretic transdermal composition according to U.S.Pat. No. 8,366,600 which suffers from the above described disadvantagescomprises

approximately 3.0% to about 5.0% sumatriptan succinate; approximately84% to about 88% water; approximately 4.0% to about 7.0% alkylatedmethacrylate co- polymer; approximately 1.0% to about 6.0% fatty acids(e.g., about 1.0% to about 5.0% lauric acid and about approximately0.05% to about 0.75% adipic acid); and approximately 0.05% to about0.75% methyl para-hydroxy benzoate.

The composition according to U.S. Pat. No. 8,366,600 exhibits anequimolar ratio between the basic groups of the polyamine (alkylatedmethacrylate co-polymer) and the acid functions of lauric acid andadipic acid (calculated with a valence of 1) so as to neutralize the pHvalue of the composition.

In the present invention lauric acid is removed from the formulation andthe necessary neutralization of the polyamine, preferably Eudragit® E100, is performed by (an increased amount of) adipic acid and/orsuccinic acid. The viscosity necessary for use in a TTS can be achievedby increasing the solids content of the solution.

In an alternative embodiment, the preferred polyamine Eudragit E 100 isreplaced by a polyamine with a different monomeric composition comparedto Eudragit E 100. Eudragit E 100 is made from three differentmethacrylate-monomers: dimethylaminoethylmethacrylate, butylmethacrylateand methylmethacrylate in a ratio of about 2:1:1. The replacementpolyamine is made of only two acrylate monomers:diethylaminoethylmethacrylate and methylmethacrylate, preferably in aratio of about 2-4 diethylaminoethylmethacrylate units to 5-8methylmethacrylate units, more preferably in a ratio of 4:6 or 3:7. Sucha polyamine is commercially available as “Kollicoat® Smartseal” fromBASF (Ludwigshafen, Germany). Kollicoat Smartseal, like Eudragit E 100,has basic functions. These basic functions, which appear protonated(polycationic) at the present pH, provide sufficient conductivity of thecomposition for iontophoretic transdermal application thereof. Thecompositions have a higher conductivity than the composition accordingto U.S. Pat. No. 8,366,600, which is an advantage, since a lower voltagecan be used for achieving the desired current flow.

The viscosity of the mass can be arbitrarily adjusted by adjusting thesolids content of the solution. Thus, the mass for dosing and transferinto the pad can be optimized. In this way, a potential leakage of thecommercial patches (due to the viscosity reduction) can be minimized.

Thus, in one embodiment, the invention pertains to a composition foriontophoretic transdermal delivery of a salt of a triptan compound,comprising:

-   -   a salt of a triptan compound, preferably a succinate    -   a polyamine    -   a dicarboxylic acid    -   water or an aqueous solvent mixture; and    -   optionally, one or more additives,

wherein this composition is free of monocarboxylic acids.

In a further embodiment, the composition comprises between 10.0 and 60.0wt.-% of one or more alkylated methacrylate polyamine copolymer(s),between 0.5 and 10 wt.-% of a salt of a triptan compound, preferablysumatriptan, between 0.5 and 10.0 wt.-% succinic acid and/or between 0.5and 10.0 wt.-% adipic acid, optionally one or more additives and water.

The invention further encompasses the use of said composition as acomponent for an iontophoretic transdermal patch.

The invention further encompasses the use of said composition in amethod for the iontophoretic transdermal administration of a triptancompound, preferably sumatriptan to subjects requiring treatment with atriptan compound.

DETAILED DESCRIPTION

The compositions according to the present invention comprise water or anaqueous solvent mixture. Preferably, the proportion of water or solventmixture is at least 30 wt.-%, more preferably 40 wt.-%, relative to thetotal weight of the composition. According to a further embodiment, thewater content or the proportion of said solvent mixture is in the rangeof 40 to 75 wt.-%.

The term “aqueous solvent mixture” generally includes liquid mixturescontaining water and at least one further solvent which is generallyselected from polar, water-miscible solvents such as, for instance,alcohols (e. g. ethanol, isopropanol, glycerol).

According to one embodiment of the invention, the polyamine is EudragitE 100, which is made from three different methacrylate-monomers:dimethylaminoethyl-methacrylate, butylmethacrylate andmethylmethacrylate in a ratio of about 2:1:1.

According to another embodiment of the invention the Eudragit E 100 isat least partially replaced by a polyamine which is preferably made frommethylmethacrylate and at least one C₁-C₄-alkylated methacrylate monomerwhich contains a di-C₁-C₃-alkylamino group. The dialkylamino group ispreferably a dimethylamino group or a diethylamino group.

A preferred replacement polyamine is a copolymer made from 5-8 monomerunits of methylmethacrylate and 2-4 monomer units ofN,N-diethylaminoethylmethacrylate. More preferred from 6 or 7 monomerunits of methylmethacrylate and 3 or 4 monomer units ofN,N-diethylaminoethylmethacrylate. Thus, a preferred replacementpolyamine has the following chemical structure:

with

m=5-8, preferably 6 or 7, and

n=2-4, preferably 3 or 4.

A specifically preferred monomeric amine isN,N-diethylamino-ethylmethacrylate. The average molecular weight of thereplacement polyamine is between 100,000 and 300,000, preferably between150,000 and 250,000, more preferred around 200,000 (measured by SEC).

Such a polyamine is commercially available as “Kollicoat® Smartseal”from BASF (Ludwigshafen, Germany).

In a further embodiment, the composition of the present invention maycomprise a combination of Eudragit E 100 and the replacement Polyamineas defined above. The weight ratio of Eudragit E 100 to the replacementPolyamine is not critical. In a preferred embodiment, however, eitherEudragit E 100 or the replacement polyamine alone is used.

Preferably, the proportion of all polyamine(s) is between 10.0 and 60.0wt.-% (based on the total weight of the composition). If Eudragit E 100is used alone its proportion is between 10.0 and 30.0 wt.-%, preferablybetween 18.0 and 26.0 wt.-% (based on the total weight of thecomposition). If Kollicoat Smartseal is used alone its proportion isbetween 30.0 and 70.0 wt.-%, preferably between 45.0 and 55.0 wt.-%(based on the total weight of the composition). This proportion ofKollicoat Smartseal is based on a dispersion which comprises 30.0 wt.-%polyamine (rest: water and small amounts of additives).

In further embodiments of the present invention, the composition furthercomprises at least one dicarboxylic acid. Monocarboxylic acids,specifically fatty acids such as lauric acid have been found to be lessadvantageous for triptan compositions for iontophoretic devices sincethey may impair the frigostability of the composition due toprecipitation.

By combining the above-discussed polyamine(s) with one or moredicarboxylic acids, corresponding polyamine salts are obtained. Thesepolyamine salts are generally water-soluble and, upon dissolution inwater, form a polymeric electrolyte. The present compositions comprisingsaid polyamine salts are particularly suitable as a carrier or reservoirfor triptans, preferably sumatriptan in iontophoretic devices.

The term “dicarboxylic acid” generally includes organic compounds thatare substituted with two carboxylic acid functional groups, whichcompounds include linear, branched and cyclic compounds, which compoundsmay be saturated or unsaturated. For instance, the dicarboxylic acid maybe selected from C₄ to C₁₀ dicarboxylic acids. Examples of dicarboxylicacids include succinic acid, glutaric acid, adipic acid and pimelicacid; succinic acid and adipic acid being preferred.

In further embodiments, the composition may contain a combinationcomprising at least two dicarboxylic acids.

Generally, the amount of dicarboxylic acid(s) is adjusted so as to be atleast sufficient to solubilize the polyamine(s), and/or other componentspresent in said composition, in order to obtain a hydrogel compositionhaving the desired properties, particularly semisolid consistency aswell as skin-adhesive properties.

Preferably, the total amount of dicarboxylic acid(s) in the compositionis between 0.5 and 10.0 wt.-%, preferably between 2.0 and 8.0 wt.-%(based on the total weight of the composition).

The term “triptan compound” includes triptan compounds, derivatives andsalts. The term also includes compounds that contain a2-(1H-indol-3-yl)-N,N-dimethylethanamine moiety. Examples of triptancompounds include, but are not limited to, almotriptan, frovatriptan,eletriptan, zolmitriptan, rizatriptan, sumatriptan, naratriptan, andpharmaceutically acceptable salts thereof. The preferred triptan issumatriptan and the preferred salt is a succinate.

As described above, the compositions of the present invention areformulated as aqueous compositions, particularly as hydrogelcompositions. In a further embodiment, the said aqueous compositionshave a pH of 3 to 8, preferably 4.0 to 6.0, or most preferably 4.5 to5.5.

Generally, it is preferred to adjust and maintain the pH in saidwater-containing compositions so that they do not substantially affectthe pH of the skin, when the compositions are applied to the skin (e. g.during transdermal or iontophoretic administration).

The composition according to the present invention may optionallycontain one or more further additives. Said additives include, but arenot limited to, additives selected from the group comprising solubilityenhancers, skin permeation enhancers, preservatives and antimicrobialagents.

In this connection, the term “solubility enhancer” generally relates tocompounds capable of increasing the solubility of the cationic activeagent within the composition. This can be achieved either by modulatingthe possible interactions between said cationic active agent and theother components present in the composition, or by additionallyincorporating suitable excipients.

Alternatively, the solubility of the active agent can be achieved bychanging its crystal modification. Examples of solubility enhancersinclude, without limitation, water; diols such as propylene glycol andglycerol; monoalcohols such as ethanol, propanol and higher alcohols;dimethylsulfoxide (DMSO), dimethylformamide, N,N-dimethylacetamide,N-substituted alkyl-azacycloalkyl-2-ones. As already described above,compounds selected from the group of dicarboxylic acids are particularlyeffective for enhancing the solubility of the polyamine(s).

Further, the term “skin permeation enhancer” particularly includescompounds capable of increasing the permeability of the skin for anactive agent contained in the composition, particularly for a cationicactive agent. Due to this increase in skin permeability, the rate atwhich the active agent(s) permeate(s) through the skin and enter(s) theblood circulation is also increased. The enhanced permeation effected bythe use of said skin permeation enhancers can be assayed and confirmedby measuring the rate of active agent diffusion through animal or humanskin using a diffusion cell apparatus generally known in the art.

Examples of permeation enhancers include, but are not limited to,dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA),decylmethylsulfoxide (C10 MSO), poly-ethylene glycol monolaurate(PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML),glycerol monolaurate (GML), lecithin, the 1-substitutedalkyl-azacycloalkyl-2-ones, particularly1-n-dodecylazacycloheptan-2-one, alcohols, and the like. The permeationenhancer may also be selected from vegetable oils, e. g. safflower oil,cotton seed oil, or corn oil. Combinations comprising two or moredifferent permeation enhancers may also be used.

Further, the term “antimicrobial agent” generally includes agents whichare capable of preventing the growth of microbes in a pharmaceuticalpreparation, particularly in a composition according to the presentinvention. Examples of suitable antimicrobials include, but are notlimited to, salts of chlorhexidine, such as iodopropynylbutylcar-bamate, diazolidinyl urea, chlorhexidine digluconate,chlorhexidine acetate, chlorhexidine isethionate, chlorhexidinehydrochloride. Other cationic antimicrobial agents may also be used,such as benzalkonium chloride, benzethonium chloride, triclocarbon,polyhexamethylene biguanide, cetylpyridinium chloride,methylbenzethonium chloride.

Other antimicrobial agents include, but are not limited to, halogenatedphenolic compounds, such as 2,4,4′-trichloro-2-hydroxy diphenyl ether(Triclosan), parachlorometa xylenol (PCMX); methyl para-hydroxybenzoate;and short-chain alcohols such as ethanol, propanol, and the like.Preferably, the total concentration of said antimicrobial agent(s) is inthe range of 0.01 to 2 wt.-%, relative to the total weight of thecomposition in which it is included.

In further embodiments, the composition may comprise between 0.01 and1.0 wt.-%, or between 0.05 and 0.5 wt.-%, or between 0.07 and 0.4 wt.-%,or between 0.08 and 0.3 wt.-%, or between 0.09 and 0.2 wt.-%, or about0.10 of methyl parahydroxybenzoate (nipagine).

According to a further embodiment, the composition of the presentinvention has adhesive properties, to ensure that the composition ismaintained in direct and complete contact with the skin at the site ofapplication during the whole time period of transdermal drugadministration. Adhesiveness can be obtained by incorporating one ormore adhesive polymers into said compositions. Adhesive polymerssuitable for this purpose are generally known to the skilled person.Preferably, a polyamine or polyamine salt having adhesive properties isused as said adhesive polymer(s).

Preferably, the compositions of the present invention are self-adhesive.To render the compositions self-adhesive, they may further contain oneor more additives selected from the group of tackifiers which groupincludes, but is not limited to, hydrocarbon resins, rosin derivatives,glycols (such as glycerol, 1,3-butanediol, propylene glycol,polyethylene glycol).

The present invention further pertains to any embodiments of the presentinvention that may result from combining two or more of theabove-described embodiments, or from combining one or more individualfeatures that are mentioned throughout the above description with anyone of the above-described embodiments of the present invention.

Generally, the compositions of the present invention can be manufacturedby conventional methods. Broadly, the compositions of the presentinvention are obtainable by dissolving or dispersing the variousingredients (i. e. triptan, polyamine, additives) in water or an aqueoussolvent mixture. The resulting mixture may then be spread on a flatsurface or poured into molds or extruded, and then allowed to solidifyto obtain hydrogel compositions having the desired shape.

The present invention further encompasses the use of the above-describedcomposition(s) as an integral component of an iontophoretic patch,preferably as an anodic reservoir of the patch. Preferably, suchcomposition is incorporated into said iontophoretic patch duringmanufacture, to form the anodic reservoir of the patch. Theabove-mentioned administration forms are obtainable by manufacturingmethods generally known in the art. EP-A 2 285 362 shows how the abovecomposition(s) may be included in a iontophoretic device.

The methods further include iontophoretic methods for transdermaladministration. Generally, the above-mentioned methods comprise a stepof applying a composition according to the present invention to the skinof said subject, and allowing the active agent e.g. sumatriptancontained in the composition to be released therefrom and to permeatethrough the skin and to enter the blood circulation of said subject.This process is enhanced by iontophoresis.

EXAMPLES

In the following, the invention and its effectiveness are illustrated bymeans of examples, together with the attached drawing.

FIG. 1 shows the viscosity degradation over time of the compositionaccording to U.S. Pat. No. 8,366,600 at 4° C. and 15° C.

Methods

Conductivity measurements were performed by a VWR EC 300 conductometer.The pH was measured by a Seven Compact pH/ion meter S220.

Viscosity measurements were performed by a Thermo Scientific HaakeRheoStress 6000 rheometer.

Experimental Procedure

The compositions were prepared with a standard laboratory equipment(stirrer, water bath, glassware). The compositions comprising Eudragit E100 were prepared as follows:

-   -   1. Reactor vessel was filled with water    -   2. methyl para-hydroxy benzoate (Nipagin) was added under        continuous stirring    -   3. Premix of Eudragit E100, lauric acid and adipic acid added        into the vessel    -   4. The solution was heated to 80° C. for 2 h while continuous        stirring    -   5. Solution was cooled down to 25° C.

The compositions with Kollicoat Smartseal were prepared first bysuspension of succinic acid in water (not completely dissolved).Afterwards, the required amounts of Kollicoat Smartseal 30D and waterwere added alternately until a visually acceptable viscosity wasreached. For the composition with adipic acid, the composition washeated to 45° C. due to the increased solubility of adipic acid athigher temperatures. In order to make verum compositions, 57.6 g of eachcomposition was added to 2.4 g sumatriptan succinate, resulting in aconcentration of 4% sumatriptan succinate.

The final composition and the measured key parameters are summarized inTables 1 (composition according to U.S. Pat. No. 8,366,600), 2(composition with replacement polyamine) and 3 (composition withEudragit E 100).

TABLE 1 Composition and parameters of the composition according to US-A8,366,600 Comparative Example (US-A 8,366,600 paragraph [0063]) Rawmaterial Amount Sumatriptan succinate 4.00% Lauric acid 3.40% Adipicacid 0.27% Eudragit E 100 5.86% Nipagin 0.10% Aqua purificata 86.37%Conductivity 4.03 mS/cm pH 5.2 Viscosity 221 mPas

TABLE 2 Compositions with Kollicoat Smartseal; lauric acid replaced byadipic or succinic acid Example 1 Example 2 Raw material Succinic acidAdipic acid Sumatriptan succinate 4.00% 4.00% Succinic acid 2.91% —Adipic acid — 3.45% Kollicoat Smartseal 30D 50.70% 48.65% Aquapurificata 42.39% 43.89% Conductivity [mS/cm] 6.14 5.05 pH 4.52 4.62Viscosity [mPas] 2180 mPas 1606 mPas

The conductivity of the compositions of Examples 1 and 2 is higher thanin the formulation according to U.S. Pat. No. 8,366,600 (ComparativeExample). Generally, a higher conductivity is less critical than a lowerconductivity, since the required voltage for the needed current islower, according to Ohm's law.

The pH of the examples 1 and 2 is lower than that of the compositionaccording to U.S. Pat. No. 8,366,600.

The viscosity of both compositions (Examples 1 and 2) was significantlyhigher than for the composition according to U.S. Pat. No. 8,366,600(Comparative Example); see FIG. 2 (Example 2). This can be considered asan advantage, since a higher viscosity may prevent the patch fromleaking during application.

Both compositions (Examples 1 and 2) were stored at 4° C. and showed nofrigoinstability over at least 2 months.

Frigostable Composition with Eudragit E 100 (Example 3)

Based on the results with Kollicoat Smartseal (Examples 1 and 2), thefrigostable composition with Eudragit E 100 (Example 3) was modified insuch way, that adipic acid was used and the solids content wasaccordingly increased. The resulting formulation and its key parametersis shown in Table 3.

TABLE 3 Frigostable compositions with Eudragit E 100 and adipic acid(Example 3) Ex. 3 Ex. 3 (dil 1) Ex. 3 (dil 2) Ex. 3 (dil 3) Ex. 3 (dil4) Ex. 3 (dil 5) Eudragit E Eudragit E Eudragit E Eudragit E Eudragit EEudragit E Raw Adipic Adipic acid Adipic acid Adipic acid Adipic acidAdipic acid material acid (diluted 1) (diluted 2) (diluted 3) (diluted4) (diluted 5) Sumatriptan 4.00% 4.00% 4.00% 4.00% 4.00% 4.00% succinateAdipic acid 7.03% 6.03% 5.93% 5.83% 5.73% 5.63% Eudragit E 100 24.12%20.67% 20.33% 19.98% 19.64% 19.29% Aqua 64.75% 69.20% 69.65% 70.09%70.54% 70.98% purificata Nipagin 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%Solids 35.25 30.80 30.36 29.91 29.47 29.02 content [%] Conductivity 5.525.67 5.81 5.70 5.74 5.70 [mS/cm] pH 4.90 5.01 4.98 4.99 5.01 4.95Viscosity 23990 1134 937 751 589 504 [mPas]

Since the viscosity of the initial composition (23990 mPas) appeared toohigh for a iontophoretic application, the composition was diluted withwater (Ex. 3 diluted 1-5) in order to reach a similar viscosity as thecompositions with Kollicoat Smartseal. As shown in Table 3, the dilutionhad only a minor impact on the conductivity and pH of the dilutedcomposition.

The composition of Example 3 (diluted 5) was physically stable at 4° C.over at least 2 months. This is shown in FIG. 3.

Preclinical Study

A preclinical study has been performed in 3 female Gottingen SPFminipigs per formulation. The three compositions according to Table 4were used in the preclinical study. Two iontophoretic transdermalpatches containing the same formulation (one activated and oneinactivated) were placed dermally on each animal for a period of 4hours. All drug pads in the patches contained 104 mg sumatriptanesuccinate. The exposure period has been 4 hours. Blood sampling wasperformed at the following time points: pre-treatment, and 15 min, 30min, 60 min, 90 min, 2, 3, 4, 4.5, 5, 6, 8, 10, 12 and 16 hourspost-treatment. Concentrations of sumatriptane in plasma samples weredetermined using solid phase extraction for sample preparation, followedby LC-MS/MS. The results of the study are shown in FIGS. 4 and 5. FIG. 4shows the time dependent plasma concentration of sumatriptane using thecompositions according to the Comparative Example and according toExample 3 (diluted 5). FIG. 5 shows the time dependent plasmaconcentration of sumatriptane using the compositions according to theComparative Example and according to Example 2a.

TABLE 4 Compositions used in the preclinical study ComparativeCompositions Example with Kollicoat (US-A Example 3 Smartseal Rawmaterial 8,366,600) (diluted 5) (Example 2a) Sumatriptan succinate 4.00%4.00% 4.00% Adipic acid 0.27% 5.63% 3.21% Lauric acid 3.40% — — EudragitE 100 5.86% 19.29% — Kollicoat Smartseat 30D — 45.20% Aqua purificata86.37% 70.98% 47.49% Nipagin 0.10% 0.10% 0.10%

FIGURES

FIG. 4: Time dependent plasma concentration of the Comparative Exampleand Example 3 (diluted 5)

FIG. 5: Time dependent plasma concentration of the Comparative Exampleand Example 2a

1. A composition for iontophoretic transdermal delivery of a salt of atriptan compound, comprising: a salt of a triptan compound, a polyamine,a dicarboxylic acid, and water or an aqueous solvent mixture whereinthis composition is free of monocarboxylic acids.
 2. The compositionaccording to claim 1, wherein the triptan compound is a compound thatcontains a 2-(1H-indol-3-yl)-N,N-dimethylethanamine moiety.
 3. Thecomposition according to claim 2, wherein the triptan compound isalmotriptan, frovatriptan, eletriptan, zolmitriptan, rizatriptan,sumatriptan or naratriptan.
 4. Composition according to claim 1, whereinthe salt is a succinate.
 5. Composition according to claim 1, whereinthe dicarboxylic acid is selected from C₄ to C₁₀ dicarboxylic acids. 6.The composition according to claim 5 wherein the dicarboxylic acid isselected from the group consisting of succinic acid, glutaric acid,adipic acid and pimelic acid.
 7. The composition according to claim 1,wherein the polyamine is made from three differentmethacrylate-monomers: dimethylaminoethyl-methacrylate,butylmethacrylate and methylmethacrylate.
 8. The composition accordingto claim 7 wherein the polyamine is partially replaced by a replacementpolyamine which has the following chemical structure:

with m=5-8 and n=2-4.
 9. The composition according to claim 8 whereinthe replacement polyamine is N,N-diethylamino-ethylmethacrylatemethylmethacrylate copolymer.
 10. The composition according to claim 1,further comprising one or more additives.
 11. An iontophoretic patchcomprising the composition of claim
 1. 12. A method of iontophoretictransdermal administration of a triptan compound comprising a step ofapplying a composition according to claim 1 to a subject's skin, andallowing the triptan compound contained in the composition to bereleased therefrom and to permeate through the skin facilitated byiontophoresis and to enter the blood circulation of said subject. 13.The composition according to claim 3, wherein the triptan compound issumatriptan.
 14. The composition according to claim 6, wherein thedicarboxylic acid is selected from the group consisting of succinic acidand adipic acid.
 15. The composition according to claim 8, wherein m=is6 or 7, and n=3 or
 4. 16. An iontophoretic patch according to claim 11,wherein an anodic reservoir of the patch comprises the composition ofclaim 1.